Activation of the central histaminergic system is involved in hypoxia-induced stroke tolerance in adult mice

• Published in: Journal of cerebral blood flow and metabolism Vol. 31; no. 1; pp. 305 - 314
• Main Authors: Fan, Yan-Ying, Hu, Wei-Wei, Dai, Hai-Bin, Zhang, Jian-Xiang, Zhang, Lu-Yi, He, Ping, Shen, Yao, Ohtsu, Hiroshi, Wei, Er-Qing, Chen, Zhong
• Format: Journal Article
• Language: English
• Published: London, England SAGE Publications 01-01-2011; Nature Publishing Group; Sage Publications Ltd
• Subjects: Animals; Biological and medical sciences; Blotting, Western; Brain Chemistry - physiology; Cerebrovascular Circulation - physiology; Chromatography, High Pressure Liquid; Cinnamates - pharmacology; Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy; Histamine - metabolism; Histamine - physiology; Histidine Decarboxylase - genetics; Histidine Decarboxylase - metabolism; Histidine Decarboxylase - physiology; Hypoxia, Brain - complications; Hypoxia, Brain - physiopathology; Infarction, Middle Cerebral Artery - pathology; Ischemic Attack, Transient - genetics; Ischemic Attack, Transient - physiopathology; Ischemic Preconditioning; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Nervous system (semeiology, syndromes); Neurology; Original; Reverse Transcriptase Polymerase Chain Reaction; Stroke - etiology; Stroke - physiopathology; Vascular diseases and vascular malformations of the nervous system; Vascular Endothelial Growth Factor A - physiology; Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors; hypoxic preconditioning; vascular endothelial growth factor; histamine; Stroke; Oxygen; Nervous system diseases; Rodentia; Cardiovascular disease; Cerebral disorder; Vascular disease; Histamine; Vertebrata; Mammalia; Mouse; Animal; Central nervous system disease; Hypoxia; Preconditioning; Cerebrovascular disease; Growth factor
• ISSN: 0271-678X; 1559-7016
• DOI: 10.1038/jcbfm.2010.94

We hypothesized that activation of the central histaminergic system is required for neuroprotection induced by hypoxic preconditioning. Wild-type (WT) and histidine decarboxylase knockout (HDC-KO) mice were preconditioned by 3 hours of hypoxia (8% O2) and, 48 hours later, subjected to 30 minutes of middle cerebral artery (MCA) occlusion, followed by 24 hours of reperfusion. Hypoxic preconditioning improved neurologic function and decreased infarct volume in WT or HDC-KO mice treated with histamine, but not in HDC-KO or WT mice treated with α-fluoromethylhistidine (α-FMH, an inhibitor of HDC). Laser-Doppler flowmetry analysis showed that hypoxic preconditioning ameliorated cerebral blood flow (CBF) in the periphery of the MCA territory during ischemia in WT mice but not in HDC-KO mice. Histamine decreased in the cortex of WT mice after 2, 3, and 4 hours of hypoxia, and HDC activity increased after 3 hours of hypoxia. Vascular endothelial growth factor (VEGF) mRNA and protein expressions showed a greater increase after hypoxia than those in HDC-KO or α-FMH-treated WT mice. In addition, the VEGF receptor-2 antagonist SU1498 prevented the protective effect of hypoxic preconditioning in infarct volume and reversed increased peripheral CBF in WT mice. Therefore, endogenous histamine is an essential mediator of hypoxic preconditioning. It may function by enhancing hypoxia-induced VEGF expression.